- Email: [email protected]
Topical ALA PDT for the treatment of severe acne vulgaris
Photodiagnosis and Photodynamic Therapy (2010) 7, 33—38
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/pdpdt
Topical ALA PDT for the treatment of severe acne vulgaris Xiu-Li Wang MD, PhD ∗, Hong-Wei Wang, Ling-Lin Zhang, Ming-Xia Guo, Zheng Huang Shanghai Skin Diseases and STD Hospital, Shanghai 200050, PR China Available online 7 February 2010
KEYWORDS Severe acne vulgaris; Aminolevulinic acid; Photodynamic therapy; Red LEDs
Summary Objectives: To evaluate the effectiveness of topical 5-aminolevulinic acid (ALA)-medicated photodynamic therapy (PDT) for the treatment of severe acne vulgaris. Methods: A total of 78 Chinese patients with Grade 4 severe facial acne were treated with 1—3 courses of ALA PDT. ALA cream (10%) was applied topically to acne lesions for 3 h. The lesions were irradiated by a LED light of 633 nm at dose levels of 50—70 J/cm2 at 66 mW/cm2 . Clinical assessment was conducted before and after treatment up to 6 months. Results: 22% of patients showed excellent improvement after one-course treatment and another 34% showed excellent improvement after two-course. The rest (44%) required three-course treatment to further reduce the number and size of residual lesions. Adverse effects were minimal. The symptoms and signs in recurrent cases (14%) were much milder and responded well to conventional topical medication. Conclusions: ALA PDT is a simple, safe and effective therapeutic option for the treatment of severe acne. Further studies to fully understand its mechanisms and optimize its effectiveness are needed. © 2010 Elsevier B.V. All rights reserved.
Introduction Acne vulgaris is the most common skin disease seen in dermatological practices worldwide. It affects many teenagers and may continue into adulthood. It is a follicular disorder that affects susceptible pilosebaceous follicules and is characterized by both non-inflammatory and inflammatory lesions [1]. Severity of acne varies markedly from patient to patient due to many factors. Although acne is not a dangerous or life-threatening condition, it is not only a cutaneous
∗
Corresponding author. E-mail address: [email protected] (X.-L. Wang).
problem, but facial acne lesions can lead to social phobia and depression. Intractable severe acne lesions can be a challenge to treat. The main etiologic factors of acne vulgaris include excessive sebum production, ductal hypercornification, and bacterial colonization associated with Propionibacterium acnes. Therefore, potential therapeutic targets are the infundibulum, sebaceous gland, P. acnes, and any of the components of the sebaceous follicle that might modulate the inflammatory response [2]. Common therapeutic modalities used in China for the treatment of acne vulgaris include vitamin A derivatives (e.g. retinoids), antibiotics, antiinflammatories, hormonal treatment (e.g. female hormones and glucocorticoid), phototherapy and chemical peels [3]. The combination of retinoids and antibiotics is often used
1572-1000/$ — see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.pdpdt.2010.01.003
34
X.-L. Wang et al.
Figure 1 Markedly improvement in a female patient treated by ALA PDT. (A) Before treatment. Inflamed pustules, nodules and cysts on the forehead with substantial tissue swelling. Some cysts merged together and formed sinuses and large lesions. (B) Intense PpIX fluorescence under UV illumination. (C) Three weeks after the 3rd course of ALA PDT. Showing the elimination of pustules, nodules and cysts. Transitional pigmentation and ice-pick scars were visible.
for severe inflammatory lesions. However, because of concerns on the systemic use of retinoids and antibiotics for certain patient populations, there is a need to develop a safe, non-invasive and effective therapy. Photodynamic therapy (PDT) is a disease site-specific treatment modality. It involves the local or systemic administration of a photosensitizer followed by irradiating the targeted disease site with non-thermal visible light. Due to their easy accessibility to photosensitizer and external light, dermatological disorders are frequent targets of PDT [4]. The potential of PDT for the treatment of local infection is also of growing interest [5]. Undoubtedly, the proof that a potent photosensitizer protoporphyrin IX (PpIX) can be generated intracellularly in sebaceous glands, hair follicles and other skin tissues after the exogenous supply of prodrug aminolevulinic acid (ALA) laid down an important foundation for developing dermatological PDT [6,7]. Early studies suggest that topical applied ALA can be converted into PpIX in acne lesions and ALA-based PDT is a potentially useful method for managing localized persistent acne and for patients unable to tolerate isotretinoin or antibiotics [8—10]. Several laser- or LED-based light sources of various wavelengths have been used in topical PDT for the treatment of moderate to severe acne. The combination of topical ALA and red LED light has been successfully used to treat several skin conditions [11]. LED offers several advantages including large uniform beam profile, reduced procedural pain and reduced cost. Longer wavelength (e.g. 630 nm) can reach the deep sebaceous glands [12]. In our previous study, we compared the effectiveness of oral retinoids and the combination of ALA and a red LED light (633 nm) for the treatment of moderate to severe acne. Results show that ALA PDT is superior to systemic retinoids in terms of efficacy and long-term control [13]. In this study, we further examined the effectiveness of topical PDT-mediated with ALA/PpIX and the red LED in the treatment of severe facial acne vulgaris in Chinese patients.
Materials and methods Patient selection Patients of both sexes who presented with severe facial acne vulgaris were enrolled in the study. Severe acne lesions were
characterized predominantly as Grade 4 lesions including inflammatory papules, pustules, nodules, scars and cysts (Figs. 1A and 2A, C and E). Some lesions were accompanied with large pus-filled cysts, substantial swelling and exfoliation around the infections. Patients with history of topical treatment or systemic antibiotics or retinoids, and history of the use of systemic steroids or anti-inflammatory drugs within the last 4 weeks were excluded from this study. Patients with a history of photosensitization or pregnancy were also excluded. No patient with large cysts had received surgical excision and drainage or interlesional corticosteroid injection. Before starting treatment, all patients were provided with an informed written consent form.
Patient demographic data A total of 78 (male = 45, female = 33, ratio = 1.36:1) consecutive patients with severe lesions was selected for ALA PDT study. The ages ranged from 16 to 37 years old (mean = 22.9 years old). The length of history ranged from 3 months to 10 years (mean = 32.2 months). All lesions were confined to the face —– mainly on the forehead, cheek and chin areas. Amongst them, 27 patients had used prescribed antibiotics systemically or topically, 17 used oral retinoids, and 3 used systemic steroids in the past. Others had tried over-thecounter products.
PpIX fluorescence imaging Before and after the topical application of ALA cream (see below), the presence of PpIX was examined under the illumination using a UV LED light source of 410 nm in the dark. The red fluorescence of PpIX was recorded by a digital camera quipped with a long pass filter.
PDT procedures Fresh ALA cream (10%, w/w) was prepared using ALA powder (Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd. Shanghai, China) and applied evenly to acne lesions plus 1 cm margin. The ALA-applied area was occluded with a cling film and covered with a black sheet for light protection. After 3 h of incubation, lesion surface was cleaned with a wet cotton gauze to remove the excess ALA and photographed as described above. The lesions were then exposed to a LED
Topical ALA PDT for the treatment of severe acne vulgaris
35
Figure 2 Markedly improvement in 3 representative patients treated by ALA PDT. (A) and (B) Before and 3 weeks after three-course of treatment of a female patient. Showing the elimination of inflammatory papules, comedones, and solitary pustules, nodules and cysts. Transitional erythema was visible. (C) and (D) Before and 2 weeks after three-course of treatment of a male patient. Showing the elimination of inflamed papules, closed comedones, and merged pustules, nodules and cysts. Mild erythema was visible. (E) and (F) Before and 2 weeks after three-course of treatment of a male patient. Showing the elimination of inflamed and exfoliative pustules, nodules and cysts. Several ice-pick scars were visible.
light panel with peak wavelength at 633 ± 6 nm (Omnilux Revive, Photo Therapeutics Ltd., Altrincham, Manchester, UK) at the dose level of 50 J/cm2 at a fixed power density of 66 mW/cm2 [13]. Patient’s eyes were protected during the light irradiation of whole face. Immediately after light irradiation, an ice cold bag was applied for 30 min to minimize pain. The treatment was repeated once for 26 patients and twice for 34 patients at 2-week intervals. The light
dose was increased to 60—70 J/cm2 for the repeated treatment.
Clinical observation and assessment Patients were examined and digital photographs taken every 2 weeks. The evaluation of clinical improvement
36 and adverse effects was carried out before and after each treatment. Clinical assessment was conducted based on the following criteria: • excellent response — >90% clearance, • good response — 50—90% clearance, and • poor response — <50% clearance or no significant response. After the completion of treatment (1—3 courses), follow up assessment was carried out every 1 month for up to 6 months for all patients.
Results PpIX production Red fluorescence generated from PpIX was observed after the topical application of 10% ALA cream for 3 h (Fig. 1B). Intense red fluorescence and therefore high PpIX accumulation was seen in lesions consisting of inflammatory papules, pustules, and cysts. Weak red fluorescence was found in comedones. Post-light irradiation examination showed the absence of PpIX fluorescence.
Adverse effects Although the ALA PDT procedures were tolerated by patients of all ages, painful feelings were a major complain. With exception of one female patient who was excluded from the study since she could not finish the treatment due to pain and discomfort, all other 77 patients completed 1—3 courses of treatment. Immediately after the light irradiation, the treated site showed edematous erythema of various degrees. An ice cold bag or cooling can be applied to minimize the pain and edema. In the next few days, the treated site would show thin crust formation as epidermal exfoliation occurred, which healed gradually without the need of medical intervention. After healing, slightly erythema or pigmentation could be visible (Fig. 2B and D) but most would disappear within 1 month after the PDT procedures without a need of intervention in most cases. About 42% of patients (32/77) showed such transient and mild hyperpigmentation. No patient had developed ulcer, scar or other significant adverse effects.
Clinical outcomes Table 1 summarized the clinical outcomes. All patients showed apparent clearance of acne lesions and improved cutaneous appearance at the treated site as shown in representative photographs (Figs. 1C and 2B, D and E). Although most patients showed limited response to previous treatment, amongst them 17 patients (22%) showed excellent improvement after one-course ALA PDT without a need of further treatment. Another 26 patients (34%) showed excellent improvement after two-course treatment. Another 34 patients (44%) required three-course treatment and all showed good to excellent improvement. These
X.-L. Wang et al. Table 1
Clinical outcomes after ALA PDT.
Cycle
N
Excellent response
Good response
Poor response
1 2 3
17 26 34
17 (22%) 26 (34%) 26 (34%)
0 0 8 (10%)
0 0 0
Total
77
69
8
0
improvements include the marked clearance of inflammatory papules, reduction in the number and size of pustules, nodules and cysts, reduction in acne activity, decrease in the production of sebum, and softening scars. No difference in the response rate was found between male and female patients. It was noticeable that the Grade and severity of residual lesions were significantly reduced after each treatment. The residual lesions responded well to conventional topical medications, such as 10% sulfacetamide sodium solution.
Follow up During 6-month follow up, 11 patients (14%) showed signs of recurrence at different time points after ALA PDT. Amongst them 2 cases occurred within 2 months, 1 case between 2 and 3 months, 4 cases between 3 and 4 months, and 6 cases after 4 months. Those reoccurred within 4 months all received 1 course of treatment. The symptoms and signs in recurrent cases were much milder and presented as papules which could be eliminated by conventional topical medications.
Discussion Photodynamic therapy is a two-step process which involves (i) a photosensitizer selectively accumulating in target tissue after local or systemic administration and (ii) activation by light in the presence of oxygen to initiate chemical reactions that generate cytotoxic species and subsequently destroy the target. In 1990 Kennedy et al. introduced the use of topical ALA-mediated PDT for the treatment of cutaneous conditions [6,7]. ALA is the natural biosynthetic precursor of heme. After topical application of ALA, it penetrates the stratum corneum and accumulates in the abnormal tissues of the epidermis and dermis and then is converted to PpIX. They showed intense red fluorescence in the sebaceous glands and weak fluorescence in the epidermis and hair follicles after intraperitoneal injection of ALA into albino mice. They demonstrated that sebaceous cells could be destroyed after exposing the mice to light. The rationale for the use of ALA PDT for the treatment of acne vulgaris was first investigated by Hongcharu et al. by using ALA (20%) and red light (550—700 nm) for treating mild to moderate acne of the back [8]. They demonstrated that inflammatory acne vulgaris could be cleared for 10 weeks and 20 weeks after one-course treatment and fourcourse treatment, respectively. Furthermore, this study also demonstrated a posttreatment reduction in sebum excretion rates, the suppression of bacterial porphyrin fluorescence
Topical ALA PDT for the treatment of severe acne vulgaris associated with colonization of P. acnes in sebaceous follicles, and the PDT damage to sebaceous glands. Since then, the effectiveness of several light sources has been evaluated in PpIX-based PDT for the treatment of mild to severe acne [9—11]. Clinical trials show there is fair evidence to support the use of these procedures for the management of moderate to severe acne [14]. ALA and its methyl derivative (methyl aminolevulinate) have also been used for the treatment of nonmelanoma skin cancer [15]. Although ALA PDT has been used in China as an off-label option for the treatment of actinic keratoses (AK), Bowen’s disease (BD), superficial squamous cell carcinoma (SCC), and basal cell carcinoma (BCC) [16], its first approved indication is condylomata acuminate [17]. Nevertheless, the first formal clinical trial of ALA PDT for the treatment of moderate to severe acne is currently being undertaken in China. Current Chinese Guideline might be summarized as the use of topical retinoids for mild lesion, oral minocycline for moderate to severe lesion, and systemic retinoids for cysts and nodules [3]. However, many patients with severe acne would refuse to use systemic retinoids and seek alternatives. Some of them could end up receiving improper treatment. In this preliminary study, we focused on evaluating the effectiveness of topical PDT in patients with severe acne lesions. We examined the effectiveness of combination of ALA (10%) and LED light (633 nm) in the treatment of Grade 4 severe facial acne vulgaris in 78 Chinese patients. Strong red PpIX fluorescence was observed in inflammatory papules, pustules, and cysts after 3 h of incubation, whereas, weak red fluorescence was found in comedones (see Fig. 1B). Nonetheless, all lesions including large and inflamed pustules, nodules and cysts (see Figs. 1 and 2) showed good to excellent response to ALA PDT although the mode of action in eliminating large pustules, solid nodules and pus-filled lumpy cysts is still unclear. Approximately 22% of patients showed excellent improvement after one-course treatment and another 34% showed excellent improvement after twocourse. Although the rest of the patients (44%) required three-course treatment, the Grade and clinical severity of residual lesions were significantly lowered and those lesions responded well to conventional topical medications. Recurrence is still a clinical challenge in acne treatment [2,18,19]. Although the combination of ALA and red LED was effective, there were 14% cases of recurrence within 6 months and half of them received 1 course of treatment. Once acne significantly improves or clears, continued treatment is still needed to keep acne from re-appearing. Nonetheless, in our case, the symptoms and signs in those recurrent lesions were much milder and could be eliminated by conventional topical medications. The severity of acute adverse effects associated with the combination of ALA and red LED light is dose-dependent. Mild to moderate edematous erythema is correlated to the increase of dermal blood concentration immediately after PDT which reaches a maximum after 1—2 days in animal model [20]. Similar acute responses were observed in this study. Although they healed gradually without medical intervention, some patients reported the loss of 2—3 work or school days due to the visibility of edema and erythema. Minimizing such effects while maintaining the therapeutic efficacy will certainly improve its acceptance [21].
37 Although the promising results from this and other studies suggest that ALA PDT might be an alternative treatment for acne, the further studies must be performed in order to develop a good and well-tolerated clinical technique regarding the number of PDT sessions and optimal drug and light doses. Furthermore, the drawback of high cost associated with ALA PDT is still a challenge to overcome [21,22]. Since the ALA PDT can effectively eliminate severe acne lesion, decrease the severity or reduce the recurrence, it might be justifiable to use ALA PDT for the management of intractable severe acne. Recent single hospital-based profile analyses in Asian populations indicate that up to 20—30% of acne patients are presented with severe lesions at the time of visiting his or her doctor [23,24], although the figure is much lower in developed nations [25]. There is certainly a need for accessible, accurate and effective (patient and physician) education on acne care and its appropriate treatment in order to reduce the incidence of severe acne and the social, healthcare and finance burdens associated with this disease. Nevertheless, the feasibility of ALA PDT for treating the severe lesions, for example the large pus-filled cyst lesion, truly deserves further validation since this approach might save many patients from surgical excision and interlesional corticosteroid injection, reduce the risk of scar formation, and provide a cost-effective alternative to conventional therapies. In conclusion, our data suggest that ALA PDT is a simple, safe and effective therapeutic option for the treatment of intractable severe acne. Further studies to understand its mechanisms, optimize its effectiveness and minimize its acute adverse responses are needed. In addition, welldesigned randomized controlled trials are also needed to offer further guidance for its use in the management of severe acne.
Acknowledgement The authors would like to thank Miss Sue Huang for her editorial assistance.
References [1] White GM. Recent findings in the epidemiologic evidence, classification, and subtypes of acne vulgaris. J Am Acad Dermatol 1998;39:s34—7. [2] van de Kerkhof PC, Kleinpenning MM, de Jong EM, Gerritsen MJ, van Dooren-Greebe RJ, Alkemade HA. Current and future treatment options for acne. J Dermatolog Treat 2006;17:198—204. [3] Task Group of Chinese Guidelines of Acne Vulgaris Treatment, Chinese Dermatological Doctor Branch of Chinese Medical Doctor Association. Chinese guidelines of acne vulgaris treatment (Discussion version), J Clin Dermatol 2008;37:339—42 [in Chinese]. [4] Huang Z. A review of progress in clinical photodynamic therapy. Technol Cancer Res Treat 2005;4:283—93. [5] O’Riordan K, Akilov OE, Hasan T. The potential for photodynamic therapy in the treatment of localized infections. Photodiag Photodyn Ther 2005;2:247—62. [6] Kennedy JC, Pottier RH, Pross DC. Photodynamic therapy with endogenous protoporphyrin IX: basic principles and present clinical experience. J Photochem Photobiol B 1990;6:143—8. [7] Divaris DX, Kennedy JC, Pottier RH. Phototoxic damage to sebaceous glands and hair follicles of mice after sys-
38
[8]
[9]
[10]
[11]
[12] [13]
[14]
[15]
X.-L. Wang et al. temic administration of 5-aminolevulinic acid correlates with localized protoporphyrin IX fluorescence. Am J Pathol 1990;136:891—7. Hongcharu W, Taylor CR, Chang Y, Aghassi D, Suthamjariya K, Anderson RR. Topical ALA-photodynamic therapy for the treatment of acne vulgaris. J Invest Dermatol 2000;115:183—92. Pollock B, Turner D, Stringer MR, et al. Topical aminolaevulinic acid-photodynamic therapy for the treatment of acne vulgaris: a study of clinical efficacy and mechanism of action. Br J Dermatol 2004;151:616—22. Mitra A, Stables GI. Topical photodynamic therapy for non-cancerous skin conditions. Photodiagn Photodyn Ther 2006;3:116—27. Szeimies RM, Matheson RT, Davis SA, et al. Topical methyl aminolevulinate photodynamic therapy using red light-emitting diode light for multiple actinic keratoses: a randomized study. Dermatol Surg 2009;35:586—92. Barolet D. Light-emitting diodes (LEDs) in dermatology. Semin Cutan Med Surg 2008;27:227—38. Zhang L, Wang X, Wang H, Su L, Guo M. Topical aminolevulinic acid-photodynamic therapy in acne. Chin J Dermatol 2009;42:78—80 [in Chinese]. Morton CA, McKenna KE, Rhodes LE, et al. Guidelines for topical photodynamic therapy: update. Br J Dermatol 2008;159:1245—66. Braathen LR, Szeimies RM, Basset-Seguin N, et al. Guidelines on the use of photodynamic therapy for nonmelanoma skin cancer: an international consensus. International Society for Photodynamic Therapy in Dermatology, 2005. J Am Acad Dermatol 2007;56:125—43.
[16] Wang XL, Wang HW, Guo MX, Xu SZ. Treatment of skin cancer and pre-cancer using topical ALA-PDT —– a single hospital experience. Photodiagn Photodyn Ther 2008;5:127— 33. [17] Huang Z. An update on the regulatory status of PDT photosensitizers in China. Photodiagn Photodyn Ther 2008;5:285—7. [18] Haider A, Shaw JC. Treatment of acne vulgaris. JAMA 2004;292:726—35. [19] Eichenfield LF, Wortzman M. A novel gel formulation of 0.25% tretinoin and 1.2% clindamycin phosphate: efficacy in acne vulgaris patients aged 12 to 18 years. Pediatr Dermatol 2009;26:257—61. [20] Juzeniene A, Nielsen KP, Zhao L, et al. Changes in human skin after topical PDT with hexyl aminolevulinate. Photodiagn Photodyn Ther 2008;5:176—81. [21] Taylor MN, Gonzalez ML. The practicalities of photodynamic therapy in acne vulgaris. Br J Dermatol 2009;160:1140—8. [22] Nouri K, Ballard CJ. Laser therapy for acne. Clin Dermatol 2006;24:26—32. [23] Yang Q, Wang F, Feng A. Analysis on effect factors of the severity of acne vulgaris. Chin J Dermatol Venereol 2009;23:425—8 [in Chinese]. [24] Adityan B, Thappa DM. Profile of acne vulgaris —– a hospitalbased study from South India. Indian J Dermatol Venereol Leprol 2009;75:272—8. [25] Tan HH, Tan AW, Barkham T, Yan XY, Zhu M. Community-based study of acne vulgaris in adolescents in Singapore. Br J Dermatol 2007;157:547—51.
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/pdpdt
Topical ALA PDT for the treatment of severe acne vulgaris Xiu-Li Wang MD, PhD ∗, Hong-Wei Wang, Ling-Lin Zhang, Ming-Xia Guo, Zheng Huang Shanghai Skin Diseases and STD Hospital, Shanghai 200050, PR China Available online 7 February 2010
KEYWORDS Severe acne vulgaris; Aminolevulinic acid; Photodynamic therapy; Red LEDs
Summary Objectives: To evaluate the effectiveness of topical 5-aminolevulinic acid (ALA)-medicated photodynamic therapy (PDT) for the treatment of severe acne vulgaris. Methods: A total of 78 Chinese patients with Grade 4 severe facial acne were treated with 1—3 courses of ALA PDT. ALA cream (10%) was applied topically to acne lesions for 3 h. The lesions were irradiated by a LED light of 633 nm at dose levels of 50—70 J/cm2 at 66 mW/cm2 . Clinical assessment was conducted before and after treatment up to 6 months. Results: 22% of patients showed excellent improvement after one-course treatment and another 34% showed excellent improvement after two-course. The rest (44%) required three-course treatment to further reduce the number and size of residual lesions. Adverse effects were minimal. The symptoms and signs in recurrent cases (14%) were much milder and responded well to conventional topical medication. Conclusions: ALA PDT is a simple, safe and effective therapeutic option for the treatment of severe acne. Further studies to fully understand its mechanisms and optimize its effectiveness are needed. © 2010 Elsevier B.V. All rights reserved.
Introduction Acne vulgaris is the most common skin disease seen in dermatological practices worldwide. It affects many teenagers and may continue into adulthood. It is a follicular disorder that affects susceptible pilosebaceous follicules and is characterized by both non-inflammatory and inflammatory lesions [1]. Severity of acne varies markedly from patient to patient due to many factors. Although acne is not a dangerous or life-threatening condition, it is not only a cutaneous
∗
Corresponding author. E-mail address: [email protected] (X.-L. Wang).
problem, but facial acne lesions can lead to social phobia and depression. Intractable severe acne lesions can be a challenge to treat. The main etiologic factors of acne vulgaris include excessive sebum production, ductal hypercornification, and bacterial colonization associated with Propionibacterium acnes. Therefore, potential therapeutic targets are the infundibulum, sebaceous gland, P. acnes, and any of the components of the sebaceous follicle that might modulate the inflammatory response [2]. Common therapeutic modalities used in China for the treatment of acne vulgaris include vitamin A derivatives (e.g. retinoids), antibiotics, antiinflammatories, hormonal treatment (e.g. female hormones and glucocorticoid), phototherapy and chemical peels [3]. The combination of retinoids and antibiotics is often used
1572-1000/$ — see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.pdpdt.2010.01.003
34
X.-L. Wang et al.
Figure 1 Markedly improvement in a female patient treated by ALA PDT. (A) Before treatment. Inflamed pustules, nodules and cysts on the forehead with substantial tissue swelling. Some cysts merged together and formed sinuses and large lesions. (B) Intense PpIX fluorescence under UV illumination. (C) Three weeks after the 3rd course of ALA PDT. Showing the elimination of pustules, nodules and cysts. Transitional pigmentation and ice-pick scars were visible.
for severe inflammatory lesions. However, because of concerns on the systemic use of retinoids and antibiotics for certain patient populations, there is a need to develop a safe, non-invasive and effective therapy. Photodynamic therapy (PDT) is a disease site-specific treatment modality. It involves the local or systemic administration of a photosensitizer followed by irradiating the targeted disease site with non-thermal visible light. Due to their easy accessibility to photosensitizer and external light, dermatological disorders are frequent targets of PDT [4]. The potential of PDT for the treatment of local infection is also of growing interest [5]. Undoubtedly, the proof that a potent photosensitizer protoporphyrin IX (PpIX) can be generated intracellularly in sebaceous glands, hair follicles and other skin tissues after the exogenous supply of prodrug aminolevulinic acid (ALA) laid down an important foundation for developing dermatological PDT [6,7]. Early studies suggest that topical applied ALA can be converted into PpIX in acne lesions and ALA-based PDT is a potentially useful method for managing localized persistent acne and for patients unable to tolerate isotretinoin or antibiotics [8—10]. Several laser- or LED-based light sources of various wavelengths have been used in topical PDT for the treatment of moderate to severe acne. The combination of topical ALA and red LED light has been successfully used to treat several skin conditions [11]. LED offers several advantages including large uniform beam profile, reduced procedural pain and reduced cost. Longer wavelength (e.g. 630 nm) can reach the deep sebaceous glands [12]. In our previous study, we compared the effectiveness of oral retinoids and the combination of ALA and a red LED light (633 nm) for the treatment of moderate to severe acne. Results show that ALA PDT is superior to systemic retinoids in terms of efficacy and long-term control [13]. In this study, we further examined the effectiveness of topical PDT-mediated with ALA/PpIX and the red LED in the treatment of severe facial acne vulgaris in Chinese patients.
Materials and methods Patient selection Patients of both sexes who presented with severe facial acne vulgaris were enrolled in the study. Severe acne lesions were
characterized predominantly as Grade 4 lesions including inflammatory papules, pustules, nodules, scars and cysts (Figs. 1A and 2A, C and E). Some lesions were accompanied with large pus-filled cysts, substantial swelling and exfoliation around the infections. Patients with history of topical treatment or systemic antibiotics or retinoids, and history of the use of systemic steroids or anti-inflammatory drugs within the last 4 weeks were excluded from this study. Patients with a history of photosensitization or pregnancy were also excluded. No patient with large cysts had received surgical excision and drainage or interlesional corticosteroid injection. Before starting treatment, all patients were provided with an informed written consent form.
Patient demographic data A total of 78 (male = 45, female = 33, ratio = 1.36:1) consecutive patients with severe lesions was selected for ALA PDT study. The ages ranged from 16 to 37 years old (mean = 22.9 years old). The length of history ranged from 3 months to 10 years (mean = 32.2 months). All lesions were confined to the face —– mainly on the forehead, cheek and chin areas. Amongst them, 27 patients had used prescribed antibiotics systemically or topically, 17 used oral retinoids, and 3 used systemic steroids in the past. Others had tried over-thecounter products.
PpIX fluorescence imaging Before and after the topical application of ALA cream (see below), the presence of PpIX was examined under the illumination using a UV LED light source of 410 nm in the dark. The red fluorescence of PpIX was recorded by a digital camera quipped with a long pass filter.
PDT procedures Fresh ALA cream (10%, w/w) was prepared using ALA powder (Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd. Shanghai, China) and applied evenly to acne lesions plus 1 cm margin. The ALA-applied area was occluded with a cling film and covered with a black sheet for light protection. After 3 h of incubation, lesion surface was cleaned with a wet cotton gauze to remove the excess ALA and photographed as described above. The lesions were then exposed to a LED
Topical ALA PDT for the treatment of severe acne vulgaris
35
Figure 2 Markedly improvement in 3 representative patients treated by ALA PDT. (A) and (B) Before and 3 weeks after three-course of treatment of a female patient. Showing the elimination of inflammatory papules, comedones, and solitary pustules, nodules and cysts. Transitional erythema was visible. (C) and (D) Before and 2 weeks after three-course of treatment of a male patient. Showing the elimination of inflamed papules, closed comedones, and merged pustules, nodules and cysts. Mild erythema was visible. (E) and (F) Before and 2 weeks after three-course of treatment of a male patient. Showing the elimination of inflamed and exfoliative pustules, nodules and cysts. Several ice-pick scars were visible.
light panel with peak wavelength at 633 ± 6 nm (Omnilux Revive, Photo Therapeutics Ltd., Altrincham, Manchester, UK) at the dose level of 50 J/cm2 at a fixed power density of 66 mW/cm2 [13]. Patient’s eyes were protected during the light irradiation of whole face. Immediately after light irradiation, an ice cold bag was applied for 30 min to minimize pain. The treatment was repeated once for 26 patients and twice for 34 patients at 2-week intervals. The light
dose was increased to 60—70 J/cm2 for the repeated treatment.
Clinical observation and assessment Patients were examined and digital photographs taken every 2 weeks. The evaluation of clinical improvement
36 and adverse effects was carried out before and after each treatment. Clinical assessment was conducted based on the following criteria: • excellent response — >90% clearance, • good response — 50—90% clearance, and • poor response — <50% clearance or no significant response. After the completion of treatment (1—3 courses), follow up assessment was carried out every 1 month for up to 6 months for all patients.
Results PpIX production Red fluorescence generated from PpIX was observed after the topical application of 10% ALA cream for 3 h (Fig. 1B). Intense red fluorescence and therefore high PpIX accumulation was seen in lesions consisting of inflammatory papules, pustules, and cysts. Weak red fluorescence was found in comedones. Post-light irradiation examination showed the absence of PpIX fluorescence.
Adverse effects Although the ALA PDT procedures were tolerated by patients of all ages, painful feelings were a major complain. With exception of one female patient who was excluded from the study since she could not finish the treatment due to pain and discomfort, all other 77 patients completed 1—3 courses of treatment. Immediately after the light irradiation, the treated site showed edematous erythema of various degrees. An ice cold bag or cooling can be applied to minimize the pain and edema. In the next few days, the treated site would show thin crust formation as epidermal exfoliation occurred, which healed gradually without the need of medical intervention. After healing, slightly erythema or pigmentation could be visible (Fig. 2B and D) but most would disappear within 1 month after the PDT procedures without a need of intervention in most cases. About 42% of patients (32/77) showed such transient and mild hyperpigmentation. No patient had developed ulcer, scar or other significant adverse effects.
Clinical outcomes Table 1 summarized the clinical outcomes. All patients showed apparent clearance of acne lesions and improved cutaneous appearance at the treated site as shown in representative photographs (Figs. 1C and 2B, D and E). Although most patients showed limited response to previous treatment, amongst them 17 patients (22%) showed excellent improvement after one-course ALA PDT without a need of further treatment. Another 26 patients (34%) showed excellent improvement after two-course treatment. Another 34 patients (44%) required three-course treatment and all showed good to excellent improvement. These
X.-L. Wang et al. Table 1
Clinical outcomes after ALA PDT.
Cycle
N
Excellent response
Good response
Poor response
1 2 3
17 26 34
17 (22%) 26 (34%) 26 (34%)
0 0 8 (10%)
0 0 0
Total
77
69
8
0
improvements include the marked clearance of inflammatory papules, reduction in the number and size of pustules, nodules and cysts, reduction in acne activity, decrease in the production of sebum, and softening scars. No difference in the response rate was found between male and female patients. It was noticeable that the Grade and severity of residual lesions were significantly reduced after each treatment. The residual lesions responded well to conventional topical medications, such as 10% sulfacetamide sodium solution.
Follow up During 6-month follow up, 11 patients (14%) showed signs of recurrence at different time points after ALA PDT. Amongst them 2 cases occurred within 2 months, 1 case between 2 and 3 months, 4 cases between 3 and 4 months, and 6 cases after 4 months. Those reoccurred within 4 months all received 1 course of treatment. The symptoms and signs in recurrent cases were much milder and presented as papules which could be eliminated by conventional topical medications.
Discussion Photodynamic therapy is a two-step process which involves (i) a photosensitizer selectively accumulating in target tissue after local or systemic administration and (ii) activation by light in the presence of oxygen to initiate chemical reactions that generate cytotoxic species and subsequently destroy the target. In 1990 Kennedy et al. introduced the use of topical ALA-mediated PDT for the treatment of cutaneous conditions [6,7]. ALA is the natural biosynthetic precursor of heme. After topical application of ALA, it penetrates the stratum corneum and accumulates in the abnormal tissues of the epidermis and dermis and then is converted to PpIX. They showed intense red fluorescence in the sebaceous glands and weak fluorescence in the epidermis and hair follicles after intraperitoneal injection of ALA into albino mice. They demonstrated that sebaceous cells could be destroyed after exposing the mice to light. The rationale for the use of ALA PDT for the treatment of acne vulgaris was first investigated by Hongcharu et al. by using ALA (20%) and red light (550—700 nm) for treating mild to moderate acne of the back [8]. They demonstrated that inflammatory acne vulgaris could be cleared for 10 weeks and 20 weeks after one-course treatment and fourcourse treatment, respectively. Furthermore, this study also demonstrated a posttreatment reduction in sebum excretion rates, the suppression of bacterial porphyrin fluorescence
Topical ALA PDT for the treatment of severe acne vulgaris associated with colonization of P. acnes in sebaceous follicles, and the PDT damage to sebaceous glands. Since then, the effectiveness of several light sources has been evaluated in PpIX-based PDT for the treatment of mild to severe acne [9—11]. Clinical trials show there is fair evidence to support the use of these procedures for the management of moderate to severe acne [14]. ALA and its methyl derivative (methyl aminolevulinate) have also been used for the treatment of nonmelanoma skin cancer [15]. Although ALA PDT has been used in China as an off-label option for the treatment of actinic keratoses (AK), Bowen’s disease (BD), superficial squamous cell carcinoma (SCC), and basal cell carcinoma (BCC) [16], its first approved indication is condylomata acuminate [17]. Nevertheless, the first formal clinical trial of ALA PDT for the treatment of moderate to severe acne is currently being undertaken in China. Current Chinese Guideline might be summarized as the use of topical retinoids for mild lesion, oral minocycline for moderate to severe lesion, and systemic retinoids for cysts and nodules [3]. However, many patients with severe acne would refuse to use systemic retinoids and seek alternatives. Some of them could end up receiving improper treatment. In this preliminary study, we focused on evaluating the effectiveness of topical PDT in patients with severe acne lesions. We examined the effectiveness of combination of ALA (10%) and LED light (633 nm) in the treatment of Grade 4 severe facial acne vulgaris in 78 Chinese patients. Strong red PpIX fluorescence was observed in inflammatory papules, pustules, and cysts after 3 h of incubation, whereas, weak red fluorescence was found in comedones (see Fig. 1B). Nonetheless, all lesions including large and inflamed pustules, nodules and cysts (see Figs. 1 and 2) showed good to excellent response to ALA PDT although the mode of action in eliminating large pustules, solid nodules and pus-filled lumpy cysts is still unclear. Approximately 22% of patients showed excellent improvement after one-course treatment and another 34% showed excellent improvement after twocourse. Although the rest of the patients (44%) required three-course treatment, the Grade and clinical severity of residual lesions were significantly lowered and those lesions responded well to conventional topical medications. Recurrence is still a clinical challenge in acne treatment [2,18,19]. Although the combination of ALA and red LED was effective, there were 14% cases of recurrence within 6 months and half of them received 1 course of treatment. Once acne significantly improves or clears, continued treatment is still needed to keep acne from re-appearing. Nonetheless, in our case, the symptoms and signs in those recurrent lesions were much milder and could be eliminated by conventional topical medications. The severity of acute adverse effects associated with the combination of ALA and red LED light is dose-dependent. Mild to moderate edematous erythema is correlated to the increase of dermal blood concentration immediately after PDT which reaches a maximum after 1—2 days in animal model [20]. Similar acute responses were observed in this study. Although they healed gradually without medical intervention, some patients reported the loss of 2—3 work or school days due to the visibility of edema and erythema. Minimizing such effects while maintaining the therapeutic efficacy will certainly improve its acceptance [21].
37 Although the promising results from this and other studies suggest that ALA PDT might be an alternative treatment for acne, the further studies must be performed in order to develop a good and well-tolerated clinical technique regarding the number of PDT sessions and optimal drug and light doses. Furthermore, the drawback of high cost associated with ALA PDT is still a challenge to overcome [21,22]. Since the ALA PDT can effectively eliminate severe acne lesion, decrease the severity or reduce the recurrence, it might be justifiable to use ALA PDT for the management of intractable severe acne. Recent single hospital-based profile analyses in Asian populations indicate that up to 20—30% of acne patients are presented with severe lesions at the time of visiting his or her doctor [23,24], although the figure is much lower in developed nations [25]. There is certainly a need for accessible, accurate and effective (patient and physician) education on acne care and its appropriate treatment in order to reduce the incidence of severe acne and the social, healthcare and finance burdens associated with this disease. Nevertheless, the feasibility of ALA PDT for treating the severe lesions, for example the large pus-filled cyst lesion, truly deserves further validation since this approach might save many patients from surgical excision and interlesional corticosteroid injection, reduce the risk of scar formation, and provide a cost-effective alternative to conventional therapies. In conclusion, our data suggest that ALA PDT is a simple, safe and effective therapeutic option for the treatment of intractable severe acne. Further studies to understand its mechanisms, optimize its effectiveness and minimize its acute adverse responses are needed. In addition, welldesigned randomized controlled trials are also needed to offer further guidance for its use in the management of severe acne.
Acknowledgement The authors would like to thank Miss Sue Huang for her editorial assistance.
References [1] White GM. Recent findings in the epidemiologic evidence, classification, and subtypes of acne vulgaris. J Am Acad Dermatol 1998;39:s34—7. [2] van de Kerkhof PC, Kleinpenning MM, de Jong EM, Gerritsen MJ, van Dooren-Greebe RJ, Alkemade HA. Current and future treatment options for acne. J Dermatolog Treat 2006;17:198—204. [3] Task Group of Chinese Guidelines of Acne Vulgaris Treatment, Chinese Dermatological Doctor Branch of Chinese Medical Doctor Association. Chinese guidelines of acne vulgaris treatment (Discussion version), J Clin Dermatol 2008;37:339—42 [in Chinese]. [4] Huang Z. A review of progress in clinical photodynamic therapy. Technol Cancer Res Treat 2005;4:283—93. [5] O’Riordan K, Akilov OE, Hasan T. The potential for photodynamic therapy in the treatment of localized infections. Photodiag Photodyn Ther 2005;2:247—62. [6] Kennedy JC, Pottier RH, Pross DC. Photodynamic therapy with endogenous protoporphyrin IX: basic principles and present clinical experience. J Photochem Photobiol B 1990;6:143—8. [7] Divaris DX, Kennedy JC, Pottier RH. Phototoxic damage to sebaceous glands and hair follicles of mice after sys-
38
[8]
[9]
[10]
[11]
[12] [13]
[14]
[15]
X.-L. Wang et al. temic administration of 5-aminolevulinic acid correlates with localized protoporphyrin IX fluorescence. Am J Pathol 1990;136:891—7. Hongcharu W, Taylor CR, Chang Y, Aghassi D, Suthamjariya K, Anderson RR. Topical ALA-photodynamic therapy for the treatment of acne vulgaris. J Invest Dermatol 2000;115:183—92. Pollock B, Turner D, Stringer MR, et al. Topical aminolaevulinic acid-photodynamic therapy for the treatment of acne vulgaris: a study of clinical efficacy and mechanism of action. Br J Dermatol 2004;151:616—22. Mitra A, Stables GI. Topical photodynamic therapy for non-cancerous skin conditions. Photodiagn Photodyn Ther 2006;3:116—27. Szeimies RM, Matheson RT, Davis SA, et al. Topical methyl aminolevulinate photodynamic therapy using red light-emitting diode light for multiple actinic keratoses: a randomized study. Dermatol Surg 2009;35:586—92. Barolet D. Light-emitting diodes (LEDs) in dermatology. Semin Cutan Med Surg 2008;27:227—38. Zhang L, Wang X, Wang H, Su L, Guo M. Topical aminolevulinic acid-photodynamic therapy in acne. Chin J Dermatol 2009;42:78—80 [in Chinese]. Morton CA, McKenna KE, Rhodes LE, et al. Guidelines for topical photodynamic therapy: update. Br J Dermatol 2008;159:1245—66. Braathen LR, Szeimies RM, Basset-Seguin N, et al. Guidelines on the use of photodynamic therapy for nonmelanoma skin cancer: an international consensus. International Society for Photodynamic Therapy in Dermatology, 2005. J Am Acad Dermatol 2007;56:125—43.
[16] Wang XL, Wang HW, Guo MX, Xu SZ. Treatment of skin cancer and pre-cancer using topical ALA-PDT —– a single hospital experience. Photodiagn Photodyn Ther 2008;5:127— 33. [17] Huang Z. An update on the regulatory status of PDT photosensitizers in China. Photodiagn Photodyn Ther 2008;5:285—7. [18] Haider A, Shaw JC. Treatment of acne vulgaris. JAMA 2004;292:726—35. [19] Eichenfield LF, Wortzman M. A novel gel formulation of 0.25% tretinoin and 1.2% clindamycin phosphate: efficacy in acne vulgaris patients aged 12 to 18 years. Pediatr Dermatol 2009;26:257—61. [20] Juzeniene A, Nielsen KP, Zhao L, et al. Changes in human skin after topical PDT with hexyl aminolevulinate. Photodiagn Photodyn Ther 2008;5:176—81. [21] Taylor MN, Gonzalez ML. The practicalities of photodynamic therapy in acne vulgaris. Br J Dermatol 2009;160:1140—8. [22] Nouri K, Ballard CJ. Laser therapy for acne. Clin Dermatol 2006;24:26—32. [23] Yang Q, Wang F, Feng A. Analysis on effect factors of the severity of acne vulgaris. Chin J Dermatol Venereol 2009;23:425—8 [in Chinese]. [24] Adityan B, Thappa DM. Profile of acne vulgaris —– a hospitalbased study from South India. Indian J Dermatol Venereol Leprol 2009;75:272—8. [25] Tan HH, Tan AW, Barkham T, Yan XY, Zhu M. Community-based study of acne vulgaris in adolescents in Singapore. Br J Dermatol 2007;157:547—51.